The B-cell receptor (BCR) is present on both normal and most malignant B-cells. Engagement of the BCR provides important survival signals, and interruption of the BCR signal can lead to B-cell death. Studies performed with siRNA to inhibit BCR expression have shown that constitutive signaling by the BCR is critical for the survival and proliferation of human B-cell lymphomas. The primary role of BCR signaling in these cells appears to be activation of spleen tyrosine kinase (Syk) which in turn leads to several downstream events that promote cell survival, including activation of Bruton tyrosine kinase (BTK), phosphatidylinositol 3 kinase (PI3K), and AKT. A number of B-cell malignancies, including diffuse large B-cell lymphomas (DLBCL), have been shown to be particularly dependent upon BCR survival signals as evidenced by their sensitivity to genetic and pharmacological inhibition of BCR signaling components in vitro. It has been shown that DLBCL cells engage PI3K, augmenting anti-apoptotic NF-kB signaling and survival signals and that inhibition of the PI3K/AKT pathway synergizes with NF-kB inhibition in killing DLBCL cell lines in vitro.
Aberrant activation of JAKs, through production of cytokines and growth factors, has also been associated with increased malignant cell proliferation and survival in a number of tumor types. JAKs activate a number of downstream pathways implicated in the proliferation and survival of malignant cells including the STATs, a family of important latent transcription factors. Of clinical relevance, levels of serum IL-10 and IL-6, which signal through the JAKs, have been found to be elevated in patients with DLBCL compared to normal controls (Gupta et al, 2012). Further, patients with high serum IL-10 levels were shown to have a shorter event-free survival (Gupta et al, 2012). Within the JAK family of kinases, JAK1 has been shown to cooperate with JAK2, JAK3, and TYK2 and to play a dominant role in mediating the signaling of a number of inflammatory cytokines including IL-6, IL-10 and interferon.
In DLBCL, JAK pathway activation occurs through both autocrine and paracrine mechanisms. In the tumor cells, BCR signaling leads to increased IL-6 and IL-10 production through activation of the NF-kB pathway (Lam et al, 2008). A subset of DLBCLs has been characterized as having high expression of STATS, IL-6, and/or IL-10 and it has been shown that JAK inhibition is cytotoxic in these DLBCL cell lines and synergizes with NF-kB inhibitors. In addition to JAK/STAT pathway activation through autocrine pathways, the stromal compartment can also provide a source of these cytokines in a paracrine manner (Hodge et al, 2005).
For these reasons, there is a need to develop new therapies that can be used to treat B-cell malignancies, such as DLBCL. This invention is directed to this need and others.